Pancreatic cancer is a lethal disease as manifested by rapid progression and early formation of regional and distant metastasis, and resistance to conventional therapies. The underlying molecular basis of pancreatic cancer progression and metastasis is unclear and has been the major focus of recent intensive investigations. Recent studies in our laboratory and others indicate that inducible nitric oxide synthase plays an important role in the regulation of pancreatic cancer progression and metastasis. We have provided causal evidence that both physiological and elevated inducible nitric oxide synthase expression and nitric oxide production in tumor suppress tumor growth and metastasis. However, we also have demonstrated a definitive inducible nitric oxide synthase activity in growing pancreatic cancer, whereas the resultant levels of nitric oxide production would have been tumor- suppressive without development of nitric oxide resistance. This critical observation led us to the identification of erythroid differentiation regulator (Erdr1) gene, which is substantially and consistently overexpressed in growing pancreatic tumors having inducible nitric oxide synthase activity. In this application, we sought to determine whether Erdr1 play a critical role in pancreatic cancer progression and metastasis. To test this hypothesis, we have designed several sets of experiments in three specific aims to determine the causal mechanistic effects of Erdr1 on the progressive growth and metastasis of pancreatic cancer;to determine whether Erdr1 upregulation is caused by nitric oxide directly;and to determine the changes of Erdr1 expression and delineate their clinical significance in human pancreatic cancer pathogenesis Our proposed studies will help better understand the mechanistic basis of pancreatic cancer progression and metastasis in general and the specific role of Erdr1 in pancreatic cancer pathogenesis in particular. As our long-term goal, the new knowledge generated from completion of our proposed studies also will aid in translational investigation of potentially effective preventive and therapeutic strategies to control human pancreatic cancer progression and metastasis. PUBLIC HEALTH RELEVANCE: Erythroid differentiation regulator is a newly identified nitric oxide-resistance-related gene in pancreatic cancer. However, the critical role of erythroid differentiation regulator and its signaling in human pancreatic cancer progression and metastasis is unclear.